Disulfiram may be an effective pharmacotherapy for cocaine dependence because it removes alcohol use as a cue to cocaine use, prevents the use of alcohol to enhance euphoria and alleviate dysphoric effects associated with binge cocaine use, and prevents the formation of cocaethylene, an active metabolite formed during cocaine-alcohol abuse whch may contribute to both euphoria and cocaine-associated toxicity. This double-blind, placebo-controlled, within subjects study (n=7) examined the effect of disulfiram treatment on acute intranasal cocaine (placebo, 1mg/kg or 2 mg/kg) administration in human volunteers. Effects of disulfiram on cocaine pharmacokinetics, physiological and behavioral responses were determined. Disulfiram treatment increased systemic exposure to cocaine with significant increases in maximal plasma cocaine contentrations. Disulfiram significantly increased cocaine-associated cardiovasuclar responses, including heart rate and blood pressure. Disulfiram treatment blunted peak "high" for cocaine 1 mg/kg dose, but increased "high" for the cocaine 2 mg/kd dose. At later time points (60 minutes after cocaine administration) both disulfiram doses accentuated negative/stimulant effects of cocaine, but responses were greatest for disulfiram 250 mg/d treatment. The production of negative effects suggest an additional rationale for disulfiram as an aversive therapy for cocaine dependence. Disulfiram 500 mg/kg alone treatment significantly increased heart rate and diastolic blood pressure and was associated with nonsignificantly greater cocaine concentrations indicating a greater potential for toxicity relative to the lower disulfiram dose. Disulfiram 250 mg/kg (or lower doses) may have potential as a pharmacotherapy for cocaine dependence, particularly in concurrent alcohol abusers. Future plans include: 1) recruitment of additional female subjects and analyzing the data while stratifying by gender and 2) conducting a study with a similar design, but using lower doses of disulfiram (125 mg daily and 62.5 mg daily) to determine whether these doses will have greater efficacy and less potential for toxic interactions with cocaine.